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UC San Diego Electronic Theses and Dissertations UC San Diego UC San Diego Electronic Theses and Dissertations Title Dissecting Enhancer Functions in Signal Induced Transcription Programs Permalink https://escholarship.org/uc/item/0n31q74b Author Hu, Yiren Publication Date 2018 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA, SAN DIEGO Dissecting Enhancer Functions in Signal Induced Transcription Programs A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Biology by Yiren Hu Committee in charge: Professor Michael Geoff Rosenfeld, Chair Professor Christopher K. Glass Professor Cornelis Murre Professor Amy Pasquinelli Professor Samuel Pfaff 2018 The Dissertation of Yiren Hu is approved, and it is acceptable in quality and form for publication on microfilm and electronically: Chair University of California, San Diego 2018 iii Table of Contents Signature Page .................................................................................................................. iii Table of Contents ............................................................................................................... iv Acknowledgements .......................................................................................................... viii Vita .......................................................................................................................................x Publications ..........................................................................................................................x Abstract of the Dissertation ............................................................................................... xi Introduction ..........................................................................................................................1 Chapter 1: Condensin I and II Complexes License Full Estrogen Receptor α-Dependent Enhancer Activation .............................................................................................................4 Chapter 2: JMJD6 Licenses Estrogen Receptor α-Dependent Enhancer and Coding Gene Activation by Modulating the Recruitment of the CARM1/ MED12 Co-activator Complex .............................................................................................................................26 Chapter 3: KDM2B and ERα Function as Dual Transcription Brakes to Curb Inflammation ......................................................................................................................59 Chapter 4: Discussion .......................................................................................................73 Appendix:Figures ..............................................................................................................78 References ........................................................................................................................134 iv List of Figures Figure 1: Estrogen-Induced Loading of Condensins to ER-α-Bound Active Enhancers, Continued ...........................................................................................................................78 Figure 2: ER-α Interacts with Condensins .........................................................................80 Figure 3: Condensin I and Condensin II Control ER-α-Regulated Gene Activation in a Partially Overlapping Manner ............................................................................................81 Figure 4: Condensins Are Needed for Full eRNA Activation and Enhancer:Promoter Looping, Continued ...........................................................................................................82 Figure 5: Condensins License Appropriate Coactivator and Corepressor Recruitment during Enhancer Activation ...............................................................................................84 Figure 6: Condensin-Dependent Recruitment of HECTD1 Is Required for E2-Induced eRNA Activation, Continued .............................................................................................85 Figure 7: Evidence Suggesting RIP140 as a Polyubiquitination Substrate of HECTD1, Continued ...........................................................................................................................87 Figure 8: JMJD6 Binding was Induced by Estrogen on ERα-Bound Active Enhancers, Continued. ........................................................................................................................101 Figure 9: JMJD6 is Required for Transcriptional Activation of ERα-Bound Active Enhancers, Continued. .....................................................................................................103 Figure 10: JMJD6 Regulates Estrogen-induced Coding Gene Transcription, Continued.105 Figure 11: JMJD6 Regulates MED12 Function in Estrogen-Induced Transcriptional Activation, Continued. .....................................................................................................107 Figure 12: JMJD6 Regulates MED12 Interaction with CARM1 and hence MED12 Methylation and Chromatin Binding, Continued. ............................................................109 Figure 13:JMJD6 is Required for Estrogen-Induced Breast Cancer Cell Growth and Tumorigenesis, Continued. ..............................................................................................111 Figure 14: A Proposed Model of JMJD6 Function in Estrogen/ERα-Regulated Enhancer and Coding Gene Activation. ...........................................................................................113 Figure 15: E2 Downregulates TNFα Transcription Program ..........................................122 Figure 16: ERα is Tethered to NFκB Enhancers to Repress Transcription .....................123 v Figure 17: KDM2B represses inflammation at basal condition .......................................124 Figure 18: KDM2B Nucleates PRC1 to Repress Inflammation ......................................125 Figure 19: KDM2B Represses Inflammation in Macrophage .........................................126 Figure 20: GRIP1 mediates ERα repressive effects on NFκB genes ...............................127 Figure S1: Additional descriptive data of condensins localization in the genome ............89 Figure S2: Additional descriptions of condensins ChIP-Seqs and their localization to active enhancers. ................................................................................................................90 Figure S3: Localization of condensins in mitotic MCF-7 cells, condensin/ER-α interaction and condensin I / II relationship, Continued. ...................................................91 Figure S4: Efficient knockdown of condensins and its effects on estrogen regulated transcription, Continued .....................................................................................................93 Figure S5: Depletion of condensins inhibits ER-α enhancer transcription, Continued. ....95 Figure S6: Depletion of condensins abolished the equilibrium of CoA/CoR recruitment to active enhancers, Continued. .............................................................................................97 Figure S7: Additional results for HECTD1 function, Continued. .....................................99 Figure S 8:JMJD6 is Recruited onto ERα-Bound Active Enhancers upon Estrogen Stimulation, Continued. ...................................................................................................114 Figure S 9:JMJD6 Determines the Transcriptional Activation of ERα-Bound Enhancers, Continued. ........................................................................................................................116 Figure S 10:JMJD6 Regulates MED12 Function in Estrogen-Induced Transcriptional Activation, Continued. .....................................................................................................118 Figure S 11:Arginine Methylation Sites Identified at the C-terminus of MED12. ..........120 Figure S 12:JMJD6 is Required for Estrogen-Induced Breast Cancer Cell Growth and Tumorigenesis. .................................................................................................................121 Figure S 13:Additional Results for E2 Down-regulates TNFα Transcription Program ..128 Figure S 14: Additional Results for ERα is tethered to NFκB enhancers to repress transcription .....................................................................................................................129 Figure S 15: Additional Results for KDM2B represses inflammation at basal condition130 vi Figure S 16: Additional Results for KDM2B Nucleates PRC1 to Repress Inflammation131 Figure S 17: Additional Results for KDM2B Represses Inflammation in Macrophage. 132 vii Acknowledgements Having Dr. Michael G. Rosenfeld as my mentor is the most valuable part of my experience at University of California, San Diego. His creative ideas, critical thinking and hardworking all set an extraordinary role model for me. I’m thankful for his encouragements that we should study the most interesting and challenging topics. I’m thankful for his high standards that we need to push research works to the most exciting level. I’m also thankful for his generous support each time when I experienced down times in graduate school. With his guidance, I’m honored to write this thesis. I want to thank my committee members Professor Cornelis Murre, Professor Christopher K. Glass, Professor
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